Lid Sheet For Use in a Blister Pack

ABSTRACT

A lid sheet for use in a blister form pack for packaging of pharmaceutical and medical products, wherein said lid sheet is a laminate comprising four layers A, B, C and D with the layer sequence A-B-C-D and the layers comprising as follows:
     (Layer A) a layer A material selected from the group consisting of cellulose material; aluminium foil; plastic film with a temperature resistance of at least 1 second at 220° C.; lacquer with a temperature resistance of at least 1 second at 220° C.; and anti-adhesive coating;   (Layer B) a layer B material selected from the group consisting of: (1) at least two non-orientated, mono-orientated or biaxially orientated plastic films displaced at an angle and bonded by means of lamination or hot calendaring or plastic coating with a net-like structure; (2) non-woven material made from a plastic polymer; (3) at least one fibre or a plastic film possessing a net-like web; (4) a foil comprising a material selected from the group consisting of Polysulfone, Polyethylenenaphthalate PEN, polyphenylsulfone (PPSU), polyimide (PI); Polyetherimide (PEI) and Tetrafluoroethylene/ethylene; and (5) a multilayer foil consisting of at least two of the aforementioned materials;   (Layer C) aluminium foil; and   (Layer D) a heat seal layer.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to EP 05 405 561.1 filed 27 Sep.2005, the disclosure of which is incorporated herein by reference in itsentirety.

TECHNICAL FIELD

The present invention relates to a lid sheet for use in a peelableblister pack and suitable for packaging of products (e.g. pharmaceuticaland medical products). The present invention in particular, relates to atear-resistant and tear propagation-resistant peelable lid sheet for usewith thermoformed and cold-formed base sheets to form such a blisterpack.

BACKGROUND TO THE INVENTION

The use of drug dispensers in the delivery of drugs to the lung iswell-known. Such dispensers generally comprise a body or housing withinwhich a drug (i.e. medicament) carrier is located. Known inhalationdevices include those in which the drug carrier is in blister pack form(e.g. an elongate blister strip) containing a number of discrete dosesof powdered drug. In use, the blister pack is typically housed withinthe dispenser in such a way that the blisters may be transported throughthe dispenser in indexed fashion to enable accessing of the discretedoses of drug carried thereby. Such devices usually contain a mechanismof individually accessing the doses contained within the blisters. Knownaccess mechanisms typically comprise either blister piercing means ormeans to peel a lid sheet away from a base sheet of the blister pack.The powdered drug can then be accessed and inhaled.

Blister packs having peelable lid sheets are also suitable for thepackaging of other products including other pharmaceutical and medicalproducts, cosmetic products, food and non-food products and for othertechnical applications.

It is desirable that the lid sheet of a peelably accessible blister packis sufficiently robust to maintain its integrity during the opening ofthe pack (e.g. by peelable separation of the lid sheet from a basesheet) within a drug dispenser. It is further desirable that such lidsheet is also sufficiently robust to maintain its integrity during thefull lifetime of use of the drug dispenser such as during any coiling orwinding up of the lid sheet once separated from the base sheet.

Known elongate peelable blister strip form drug packs for use incontaining inhalable drug in dry powder form are described inApplicant's pending PCT Patent Application No. WO2004/041672. The lidsheet thereof typically comprises a laminate including at least thefollowing successive layers: (a) paper; bonded to (b) plastic polymericfilm; bonded to (c) aluminium foil. The plastic polymeric film layersuitably comprises a material selected from the group consisting ofpolyester, polyamide, polypropylene and PVC. Typically, the aluminiumfoil layer of the lid sheet is further provided with a layer of heatseal lacquer, which bonds with the inner layer of the base sheet. Thatbond is disrupted during opening of the blister strip by peelableremoval of the lid sheet from the base sheet.

Other known peelable blister form packaging pharmaceutical and medicalproducts with a protective function against humidity, gases and lighttypically have the following structure:

-   -   Lacquered/aluminium foil>30 μm/seal layer    -   Paper, 40-50 g/m²/aluminium foil, 20-30 μm/seal layer    -   OPA or PET film, 12-25 μm/aluminium foil, 20-25 μm/seal layer    -   Paper, 20-50 g/m²/OPA or PET film, 12-25 μm/aluminium foil,        20-25 μm/Seal layer

The Applicant has now found that the robustness of the lid sheet may beenhanced by the use of particular, unconventional polymeric materialsfor use in laminate sheets thereof that are additional to the paper andaluminium foil layers. In particular, the tear resistance and tearpropagation resistance of the lid sheet during use may be enhanced.Improved blister form drug packs including such lid sheets may thereby,be achieved.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a lidsheet for use in a blister form pack for packaging of (e.g.pharmaceutical and medical) products, wherein said lid sheet is alaminate comprising four layers A, B, C and D with the layer sequenceA-B-C-D and the layers comprising as follows:

(Layer A) a layer A material selected from the group consisting ofcellulose material (e.g. cellulose film or paper); aluminium foil;plastic film with a temperature resistance of at least 1 second at 220°C.; lacquer with a temperature resistance of at least 1 second at 220°C.; and anti-adhesive coating;(Layer B) a layer B material selected from the group consisting of atleast two non-orientated, mono-orientated or biaxially orientatedplastic films displaced at an angle and bonded by means of lamination orhot calendaring or plastic coating with a net-like structure; non-wovenmaterial made from a plastic polymer; at least one fibre or a plasticfilm possessing a net-like web; a foil comprising a material selectedfrom the group consisting of Polysulfone, Polyethylenenaphthalate PEN,polyphenylsulfone (PPSU), polyimide (PI); Polyetherimide (PEI) andTetrafluoroethylene/ethylene; and a multilayer foil consisting of atleast two of the aforementioned materials;(Layer C) aluminium foil; and(Layer D) a heat seal layer (e.g. a heat seal film, a heat sealextrusion coating or a heat seal lacquer).

The lid sheet (‘cover foil’) herein is suitable for use as atear-resistant and tear propagation-resistant peelable lid sheet, forexample for use with thermoformed and cold-formed base sheets to form ablister pack for packaging of products including pharmaceutical andmedical products, cosmetic products, food and non-food products and forother technical applications.

These and other embodiments of the present invention are set forth inthe later description, which describes for illustrative purposes onlyvarious embodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

Suitably, layers A and B and layers B and C are bonded using alaminating aid to achieve a bond strength of at least 2N/15 mm. Suitablelaminating aids are chosen such that during peelable opening of theblister pack no delamination of the laminate occurs.

For example, laminating aids can be:

-   -   Aqueous, solvent-free or solvent-based single or multi component        adhesives or    -   Extrusion resin as a monolayer or coextruded.

Surprisingly it was found that the combination of individual materialswith different physical and special mechanical properties runninglengthwise and crossways to the machine direction together with thelayers made from aluminium and heat seal lacquer provided a lid sheet ofsuitable robustness.

Layers A to D have the following functions, in particular:

-   -   Layer A: Prevention of adhesion of the laminate on the sealing        machine    -   Layer B: Prevention of tear and tear propagation of the cover        foil during opening    -   Layer C: Carrier with a barrier effect against humidity, gases        and light    -   Layer D: Sealing layer for peelable opening

The paper of layer A can be untreated, coated or satined (calendared)and suitably has a weight of from 15 to 100 g/m², preferably from 20 to50 g/m².

The aluminium foil of layer A suitably has a thickness of from 6 to 60μm, preferably from 7 to 25 μm.

The temperature-resistant plastic film of layer A suitably has athickness of from 7 to 25 μm, preferably from 12 to 25 μm.

The temperature-resistant plastic film of layer A by way of exampleconsists of Polyethylenterephthalate (PET), orientated Polyamide (OPA),Polysulfone (PSU), Polyphenylsulfone (PPSU), Polyaryletherketone (PEEK),Polyimide (PI) or Polyetherimide (PEI) with a suitable thickness of from7 to 25 μm, preferably from 12 to 25 μm.

The plastic films of layer B consist for example of Polyethylene (PE),in particular VLDPE, LLDPE, LMDPE, LDPE or HDPE, Polypropylene (PP),Polyester, Polyamide (PA), Polystyrene (PS), Polycarbonate (PC),halogen-containing plastics; in particular Polyvinylchloride (PVC),Polyvinylidenchloride (PVDC), or Polychlorotrifluoroethylene (PCTFE),Poly-Acrylic-Nitrile (PAN), Tetrafluoroethylene/ethylene or acombination of the aforementioned plastics and suitably have a thicknessof from 8 to 200 μm, preferably from 12 to 100 μm. Suitable plasticfilms might have a woven structure.

The plastic coating of the net-like structure of layer B consistspreferably of Polyetheylene (PE), in particular VLDPE, LLDPE, LMDPE,LDPE, or HDPE, Polypropylene (PP), Polyester, Polyamide (PA),halogen-containing plastics, in particular Polyvinylchloride (PVC),Polyvinylidenchloride (PVDC) or Polychlorotrifluoroethylene (PCTFE) oralbumen (silk) and has a preferred weight of from 30 to 150 g/m2,particularly from 40 to 120 g/m². Suitable plastic coatings might have awoven structure.

The non-woven material of layer B consists for instance of HDPE (e.g.Tyvec®), Polyester (e.g. Spunbond® or Evolon®) Polyethylenterephthalate(PET)/Polybutylenterephthalate (PBT) with Polyamide 6 or Polyamide 6.6,Polyester with polyolefines, in particular PET with PP or Polyamide withpolyolefines and suitably possesses preferably a surface weight of from10 to 120 g/m².

The foil consisting of at least one fibre or a plastic film having anet-like web (e.g. woven) of layer B consists for instance ofPolyethylene (PE), in particular VLDPE, LLDPE, LMDPE, LDPE or HDPE,Polypropylene (PP), Polyester, Polyamide (PA), Polystyrene (PS),Polycarbonate (PC), halogen-containing plastics, in particularPolyvinylchloride (PVC), Polyvinylidene chloride (PVDC) orPolychlorotrifluoroethylene (PCTFE), Poly-Acrylic-Nitrile (PAN),Tetrafluorothylene/ethylene or a combination of the aforementionedplastics and has a suitable thickness of from 8 to 200 μm, preferablyfrom 12 to 80 μm.

The individual films of the multilayer foil of layer B consist forinstance of Polyethylene (PE), in particular VLDE, LLDPE, LMDPE, LDPE orHDPE, Polypropylene (PP), Polyester, Polyamide (PA), Polystyrene (PS),Polycarbonate (PC), halogen-containing plastics, particularlyPolyvinylchloride (PVC). Polyvinylidenchloride (PVDC) orPolychlorotrifluoroethylene (PCTFE), Poly-Acrylic-Nitrile (PAN),Tetrafluoroethylene/ethylene or a combination of the aforementionedplastics and have a thickness of 8 to 200 μm, preferably 12 to 75 μm.

The aluminium foil of layer C preferably has a suitable thickness offrom 7 to 60 μm, preferably from 9 to 30 μm.

As a heat sealing lacquer medium, lacquers, plastic foils, and coatingscan be used which allow an air-tight seal of the lid sheet (‘coverfoil’) to the inside of the base sheet and at the same time allowremoval of the lid sheet by peeling.

Overprinting of both the lid sheet and the base sheet is possible.

There is also provided a blister form pack for packaging ofpharmaceutical and medical products comprising

(a) a base sheet in which blisters are formed to define pockets therein;and(b) a lid sheet as defined herein, and which is sealable to the basesheet (e.g. except in the region of the blisters) and mechanicallypeelable from the base sheet.

There is further provided a blister form drug pack (e.g. a formed pack)comprising

(a) a base sheet in which blisters are formed to define pockets thereinfor the containment of inhalable drug;(b) a lid sheet which is sealable to the base sheet (e.g. except in theregion of the blisters) and mechanically (e.g. manually) peelable fromthe base sheet to enable release of said inhalable drug,wherein said lid sheet has a laminate structure comprising at least thefollowing successive layers:(i) an outer paper lid sheet layer; bonded to(ii) a first intermediate lid sheet layer of polymeric material; bondeddirectly or indirectly to(iii) an aluminium foil lid sheet layer; bonded directly or indirectlyto(iv) an inner lid sheet heat seal layer (e.g. a heat seal film, a heatseal extrusion coating or a heat seal lacquer).

There is provided a blister form drug (i.e. medicament) pack comprisinga base sheet and a lid sheet, each of the base and lid sheet having aparticular form as described in more detail hereinafter.

In embodiments, the drug pack has multiple distinct (i.e. separate) drugdoses carried thereby, and may for example, be in the form of anelongate blister strip, disk or other suitable blister pack form.Preferably, the drug pack is in the form of an elongate blister strip.

The base sheet is provided with blisters that define pockets for thecontainment of inhalable drug. The pockets may define any suitableprofile including those with a square, circular or rectangular profileor rounded-corner variations of the square and rectangular profiles. Inembodiments, two or more pockets could be linked with a channel thatduring the process of inhalation the powder will come together. The term‘inhalable drug’ is used herein to mean drug suitable for inhaleddelivery to the lung.

The lid sheet is sealable to the base sheet except in the region of theblisters and mechanically (e.g. manually) peelable from the base sheetto enable release of the inhalable drug from an opened pocket.

Preferably, the drug pack is in the form of an elongate blister strip.The elongate blister strip comprises an elongate strip form base sheet,in which blisters are formed to define pockets therein for thecontainment of inhalable drug. Typically, one or more series of blistersare arranged (e.g. in linear series arrangement or zig-zag or circulararrangement) along the length of the base sheet. The lid sheet is sealed(e.g. hermetically) to the base sheet except in the region of theblisters in such a manner that the lid sheet and the base sheet can bepeeled apart to enable release of the inhalable drug from one or morepockets thereof.

The base and lid sheets are typically sealed to one another over theirwhole width except for the forward end portions where they are typicallynot sealed to each other at all. Thus, separate base and lid sheetforward end portions are presented at the forward end of the elongateblister strip. The sealing can be done by all known sealing techniques(rotary, intermittent and a combination of flat bed and sealing roller).The bonding of the lid sheet to the base sheet can be done by all knowntechniques, e.g. contact heating, ultrasonic welding.

In embodiments, both the lid sheet and the base sheet of the drug packherein are in the form of a laminate, which comprises multiple layers ofdifferent materials. In other embodiments, the base sheet comprises asingle material.

The base sheet herein typically comprises (i) a first base sheet layerof aluminium foil; and (ii) a second base sheet layer of polymericmaterial of thickness from 10 to 150 micron.

Typically, the second base sheet layer is arranged to bond to the innerlid sheet layer and this bond allows for peelable separation of theselayers.

The first base sheet layer of aluminium foil typically has a thicknessof from 15 to 120 micron, particularly 20 to 90 micron.

The thickness of the second base sheet layer of polymeric material isfrom 10 to 150 micron such as from 10 to 120 micron, preferably from 15to 100 micron.

In embodiments, the second base sheet layer comprises a polymericmaterial of low water vapour permeability. In embodiments, the watervapour permeability is less than 0.6 g/(100 inches²) (24 hours) (mil) at25° C., preferably less than less than 0.3 g/(100 inches²) (24 hours)(mil) at 25° C. as suitably measured by ASTM E96-635 (E) which defines astandard test method for measuring water vapour permeability.

In embodiments, the polymeric material of the second base sheet layercomprises a material selected from the group consisting of polyvinylchloride (PVC) (e.g. in oriented or cast form); polypropylene (e.g. inoriented or cast form; standard or metallocene); polyethylene (e.g. inhigh, low or intermediate density form; standard or metallocene);polyvinylidene chloride (PVDC); polychlorotrifluoroethylene (PCTFE);cyclic olefin copolymer (COC); and cyclic olefin polymer (COP).Optionally, other layers of material are also present.

Material sold under the tradename Aclar by Honeywell Inc, a UnitedStates corporation is a suitable polychlorotrifluoroethylene (PCTFE)polymeric material herein. Suitable cyclic olefin copolymer (COC) issold by Hoechst AG of Germany, under the trade name Topaz. A suitablecyclic olefin polymer is sold by Nippon Zeon Co. Ltd of Tokyo, Japanunder the trade name Zenor.

In embodiments, polypropylene polymeric material and polyethylenepolymeric material is manufactured by a process in which a one or moremetallocene compounds is employed to modify and/or control the nature ofany side-chain groups thereof.

Where the polymeric material of the second base sheet layer is selectedfrom the group consisting of polyethylene (in high density form),polypropylene or polyvinylidene chloride (PVDC), reduced oxygenpermeation through the polymeric layer, and hence to the interior of theblister, may be achieved. Oxygen permeation through the polymeric layermay be tested using ASTM test method D3985-81, in which such oxygentransmission is measured at 25° C. and 50% Relative Humidity.

In embodiments, the first base sheet layer of aluminium foil is providedwith an outer base sheet layer of a polymeric material, particularlyoriented polyamide (OPA). Thus, the base sheet comprises an outer layerof oriented polyamide (OPA), which bonds to (i) the first base sheetlayer of aluminium foil; which bonds to (ii) the second base sheet layerof polymeric material of thickness from 10 to 100 micron.

The bonding between layers of the base sheet is suitably provided as anadhesive bond (e.g. solvent-based adhesive wherein the solvent isorganic or water-based); solvent free adhesive bond; extrusion laminatedbond; or heat calendaring.

One particular base sheet comprises the following successive layers: (a)oriented polyamide (OPA); adhesively bonded to (b) aluminium foil;adhesively bonded to (c) polyvinyl chloride (PVC). The thickness of thepolyvinyl chloride (PVC) layer is from 10 to 100 micron, particularlyfrom 50 to 100 micron.

Another particular base sheet comprises the following successive layers:(a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil;adhesively bonded to (c) polyester. The thickness of the polyester layeris from 10 to 100 micron, particularly from 50 to 100 micron.

Another particular base sheet comprises the following successive layers:(a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil;adhesively bonded to (c) polypropylene. The thickness of thepolypropylene layer is from 10 to 100 micron, particularly from 50 to100 micron.

Another particular base sheet comprises the following successive layers:(a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil;adhesively bonded or extrusion laminated to (c) oriented polypropylene(OPP). The thickness of the oriented polypropylene (OPP) layer is from10 to 60 micron, particularly from 20 to 30 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) cast polypropylene. The thickness of thecast polypropylene layer is from 10 to 60 micron, particularly from 20to 30 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded or extrusion laminated to (c) high densitypolyethylene (HDPE). The thickness of the high density polyethylene(HDPE) layer is from 10 to 100 micron, particularly from 30 to 70micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded or extrusion laminated to (c) low densitypolyethylene (LDPE). The thickness of the low density polyethylene(LDPE) layer is from 10 to 80 micron, particularly from 20 to 50 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) polyvinylidene chloride (PVDC). Thethickness of the polyvinylidene chloride (PVDC) layer is from 10 to 60micron, particularly from 20 to 30 micron. The grade of the PVDC isgenerally from 8 to 95 gsm, particularly from 10 to 40 gsm.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) polychlorotrifluoroethylene (PCTFE). Thethickness of the polychlorotrifluoroethylene (PCTFE) layer is from 10 to60 micron, particularly from 20 to 45 micron. Thepolychlorotrifluoroethylene (PCTFE) layer can be oriented.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded or extrusion laminated to (c) cyclic olefincopolymer (COC). The thickness of the cyclic olefin copolymer (COC)layer is from 10 to 60 micron, particularly from 20 to 30 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded or extrusion laminated to (c) cyclic olefinpolymer (COP). The thickness of the cyclic olefin polymer (COP) layer isfrom 10 to 60 micron, particularly from 20 to 30 micron.

The lid sheet of the drug pack herein has a particular laminatestructure.

In one aspect herein, the lid sheet has a laminate structure comprisingat least the following successive layers:

(i) an outer lid sheet layer of cellulose material (e.g. paper orcellulose film); bonded to(ii) a first intermediate lid sheet layer of polymeric material; bondeddirectly or indirectly to(iii) an aluminium foil lid sheet layer; bonded directly or indirectlyto(iv) an inner lid sheet heat seal layer (e.g. a heat seal film, a heatseal extrusion coating or a heat seal lacquer).

The thickness of each of the layers of the lid sheet may be selectedaccording to the desired properties but is typically of the order offrom 3 to 200 micron, particularly from 5 to 50 micron.

The outer paper lid sheet layer typically comprises paper of gauge from10 to 80 g/m², particularly from 20 to 50 g/m².

The first intermediate lid sheet layer of polymeric material addsstrength to the lid sheet to improve tear resistance and tearpropagation resistance. The first intermediate lid sheet layer ofpolymeric material suitably has a thickness of from 5 to 100 micron,particularly 10 to 80 micron.

In one aspect, the first lid sheet intermediate layer of polymericmaterial comprises woven polyamide, which for example defines a net-likeweb structure. The interply bonding of the woven polyamide layer to itsadjacent layers is suitably achieved as an adhesive lamination or as anextrusion lamination.

One particular lid sheet comprises (i) an outer paper lid sheet layer;bonded to (ii) a first intermediate lid sheet layer of woven polyamidematerial of thickness from 50 to 120 micron, particularly from 50 to 100micron; bonded to (iii) an aluminium foil lid sheet layer; bonded to(iv) an inner lid sheet layer of heat seal lacquer.

In another aspect, the optional first intermediate layer of polymericmaterial comprises spun poly (ethylene terephthalate) (spun-PET), whichis a non-woven material. The spun-PET is typically of weight from 10 to250 g/m², particularly from 20 to 60 g/m². The interply bonding of thespun-PET layer is suitably achieved using an extrusion lamination,particularly polyethylene (PE) extrusion. Suitable spun-PET materialsinclude those sold by Johns Manville of Waterville, Ohio under the tradenames spunbond 488/20, spunbond 488/30 and spunbond 088/30.

One particular lid sheet comprises (i) an outer paper lid sheet layer;bonded using PE extrusion to (ii) a first intermediate lid sheet layerof spun-PET material of weight from 10 to 80 g/m²; bonded using PEextrusion to (iii) an aluminium foil lid sheet layer; bonded to (iv) aninner lid sheet layer of a heat seal lacquer, a heat seal film or a heatseal extrusion coating.

Another particular lid sheet comprises (i) an outer paper lid sheetlayer; bonded using extrusion lamination to (ii) a first intermediatelid sheet layer of spun-PET material of weight from 10 to 80 g/m²;bonded using co-extrusion lamination (one or two co-extrusion layers) to(iii) an aluminium foil lid sheet layer; bonded to (iv) an inner lidsheet layer of a heat seal lacquer, a heat seal film or a heat sealextrusion coating.

Another particular lid sheet comprises (i) an outer paper lid sheetlayer; bonded using lacquer lamination to (ii) a first intermediate lidsheet layer of spun-PET material of weight from 10 to 80 g/m²; bondedusing lacquer lamination to (iii) an aluminium foil lid sheet layer;bonded to (iv) an inner lid sheet layer of a heat seal lacquer, a heatseal film or a heat seal extrusion coating.

In another aspect, the optional first intermediate layer of polymericmaterial comprises spun high density polyethylene (spun-HDPE), which isa non-woven material. The spun-HDPE is typically of weight from 10 to 80g/m², particularly from 20 to 60 g/m². The interply bonding of thespun-HDPE is suitably achieved using an extrusion lamination,particularly polyethylene (PE) extrusion. The material sold by Du Pontunder the trade name Tyvek is a suitable spun-HDPE sheet material.

One particular lid sheet comprises (i) an outer paper lid sheet layer;bonded using PE extrusion to (ii) a first intermediate lid sheet layerof spun-HDPE material of weight from 10 to 80 g/m²; bonded using PEextrusion to (iii) an aluminium foil lid sheet layer; bonded to (iv) aninner lid sheet layer of a heat seal lacquer, a heat seal film or a heatseal extrusion coating.

In another aspect, the optional first intermediate layer of polymericmaterial comprises cross-laminated high density polyethylene (HDPE). Bycross-laminated HDPE it is meant a material comprising at least two HDPEfilms cross-laminated to each other at a suitable cross-laminationangle, wherein the cross-lamination angle is typically from 30 to 600,particularly 450. The cross-laminated HDPE is typically of thicknessfrom 30 to 100 micron, particularly from 50 to 80 micron. The materialsold by Illinois Tool Works, Inc. under the trade name Valeron is asuitable cross-laminated HDPE material herein.

One particular lid sheet comprises (i) an outer paper lid sheet layer;bonded to (ii) a first intermediate lid sheet layer of cross-laminatedHDPE material of thickness from 30 to 100 micron, particularly from 50to 80 micron; bonded to (iii) an aluminium foil lid sheet layer; bondedto (iv) an inner lid sheet layer of a heat seal lacquer, a heat sealfilm or a heat seal extrusion coating.

In another aspect, the optional first intermediate layer of polymericmaterial comprises cross-laminated polyethylene terephthalate (PET). Bycross-laminated PET it is meant a material comprising at least two PETfilms cross-laminated to each other at a suitable cross-laminationangle, wherein the cross-lamination angle is typically from 30 to 600,particularly 450. The cross-laminated PET is typically of thickness from30 to 100 micron, particularly from 50 to 80 micron.

One particular lid sheet comprises (i) an outer paper lid sheet layer;bonded to (ii) a first intermediate lid sheet layer of cross-laminatedPET material of thickness from 30 to 100 micron, particularly from 50 to80 micron; bonded to (iii) an aluminium foil lid sheet layer; bonded to(iv) an inner lid sheet layer of a heat seal lacquer, a heat seal filmor a heat seal extrusion coating.

The thickness of the aluminium foil lid sheet layer is typically from 10to 60 micron, particularly 15 to 40 micron.

The aluminium foil lid sheet layer bonds directly or indirectly to theinner lid sheet heat seal layer. When bonded indirectly, one or moreadditional intermediate lid sheet layers sandwich between the aluminiumfoil lid sheet layer and the inner lid sheet heat seal layer.

The inner lid sheet heat seal layer is arranged for bonding to the basesheet, typically to the second base sheet layer of polymeric material.

The bonding between layers of the lid sheet is suitably provided as anadhesive bond (e.g. solvent-based adhesive wherein the solvent isorganic or water-based); solvent free adhesive bond; extrusion laminatedbond; or heat calendaring.

According to another aspect of the present invention there is provided ablister form drug pack comprising

(a) a base sheet in which blisters are formed to define pockets thereinfor the containment of inhalable drug;(b) a lid sheet which is sealable to the base sheet except in the regionof the blisters and mechanically peelable from the base sheet to enablerelease of said inhalable drug,wherein said lid sheet has a laminate structure comprising at least thefollowing successive layers:(i) an outer lid sheet layer of cellulose material (e.g. paper orcellulose film); bonded directly or via an optional first intermediatelayer of polymeric material to(ii) an aluminium foil lid sheet layer; bonded to(iii) an inner lid sheet layer of polymeric material.

In this aspect, the base sheet may comprise any of the previouslydescribed base sheet laminate structures; the outer paper lid sheetlayer typically comprises paper of gauge from 10 to 80 g/m²,particularly from 20 to 50 g/m²; and the thickness of the aluminium foillid sheet layer is typically from 10 to 60 micron, particularly 15 to 40micron.

The outer lid sheet layer of cellulose material (e.g. paper or cellulosefilm) bonds directly or via an optional first intermediate layer ofpolymeric material to the aluminium foil lid sheet layer. In variationsherein, the outer paper lid sheet layer is absent.

In aspects, the (iii) inner lid sheet layer does not comprise a heatseal lacquer component but rather another polymeric material (e.g. afilm or extrusion coating). When this is so, the lid sheet is mostsuitable for use with a base sheet that has heat seal lacquer or anothersubstance capable of providing peel function provided as its inner basesheet layer.

In one aspect, the optional first intermediate layer of polymericmaterial comprises a polyethylene (PE) extrusion layer and the inner lidsheet layer of polymeric material comprises a peelable co-extrusioncoating (e.g. polyethylene/polybutylene). Examples of other suitablepeelable co-extrusion coating materials include those produced by AlcanPackaging Singen GmbH: (1) Intermediate extrusion layer (APS-referenceNo. X2228EX): a copolymerisate of ethylene and ethylene acrylic acidprovided by DOW Plastics; and (2) Co-extrusion coating (of APS-referenceNo. X2253EX and X2311EX) where X2253EX is a random terpolymer ofethylene, butylacrylate and maleic anhydride provided by Arkema andX2311EX is a mixture of polyethylene provided by Shuman and a copolymerof ethylene and acrylic ester provided by Arkema.

One suitable drug pack thus, comprises (i) an outer paper lid sheetlayer; bonded via an optional first intermediate layer of polyethylene(PE) extrusion to (ii) an aluminium foil lid sheet layer; bonded to(iii) an inner lid sheet layer of peelable co-extrusion coating having aweight of from 5 to 50 g/m², particularly from 10 to 30 g/m².

In embodiments, the inner lid sheet layer of polymeric materialcomprises a peel film. The peel film is for example, a polyethylene (PE)peel film, a polyvinyl chloride (PVC) peel film or a polypropylene (PP)peel film. This peel film is particularly suitable for peelable sealingto an inner base sheet layer comprising polyvinyl chloride (PVC) orpolyethylene (PE).

A suitable peel film for sealing onto polyethylene (PE) is produced byNordenia Gronau GmbH of Germany (Alcan trade reference FSN097). Asuitable peel film for sealing onto polyvinyl chloride (PVC) is producedby Nordenia Gronau GmbH of Germany (Alcan trade reference X3496FSN).

In one aspect, no optional first intermediate layer of polymericmaterial is present and the inner lid sheet layer of polymeric materialcomprises a peel film (e.g. a polyethylene (PE) peel film, a polyvinylchloride (PVC) peel film or a polypropylene (PP) peel film).

One suitable lid sheet thus, comprises (i) an outer paper lid sheetlayer; bonded to (ii) an aluminium foil lid sheet layer; bonded to (iii)an inner lid sheet layer of polyethylene (PE) peel film of thicknessfrom 10 to 80 micron, particularly from 15 to 50 micron. This lid sheetis particularly suitable for use with a base sheet having PE peel filmas its inner base sheet layer.

A further suitable lid sheet thus, comprises (i) an outer paper lidsheet layer; bonded to (ii) an aluminium foil lid sheet layer; bonded to(iii) an inner lid sheet layer of poly vinyl chloride (PVC) peel film ofthickness from 10 to 80 micron, particularly from 15 to 50 micron.

In a further aspect, the optional first intermediate layer of polymericmaterial comprises polyethylene terephthalate (PET) and the inner lidsheet layer of polymeric material comprises polyvinyl chloride (PVC).

One suitable drug pack thus, comprises (i) an outer paper lid sheetlayer; bonded via an optional first intermediate layer of PET ofthickness from 5 to 30 micron, particularly 10 to 25 micron bonded to(ii) an aluminium foil lid sheet layer; bonded to (iii) an inner lidsheet layer of PVC of thickness from 5 to 50 micron, particularly from10 to 40 micron. This lid sheet is particularly suitable for use with abase sheet having heat seal lacquer as its inner base sheet layer.

In a further aspect, the optional first intermediate layer of polymericmaterial comprises spun poly (ethylene terephthalate) (spun-PET) and theinner lid sheet layer of polymeric material comprises a peel film (e.g.a polyethylene (PE) peel film, a polyvinyl chloride (PVC) peel film or apolypropylene (PP) peel film). This lid sheet is particularly suitablefor use with a base sheet having PVC as its inner base sheet layer. Thespun-PET is typically of weight from 10 to 250 g/m², particularly from20 to 60 g/m². The interply bonding of the spun-PET layer is suitablyachieved using an extrusion lamination, particularly polyethylene (PE)extrusion. Suitable spun-PET materials include those sold by JohnsManville under the trade names spunbond 488/20, spunbond 488/30 andspunbond 088/30.

One suitable drug pack thus, comprises (i) an outer paper lid sheetlayer; bonded via an optional first intermediate layer of spun-PET ofthickness from 10 to 60 micron, particularly 20 to 30 micron bonded to(ii) an aluminium foil lid sheet layer; bonded to (iii) an inner lidsheet layer of a peel film of thickness from 5 to 50 micron,particularly from 10 to 40 micron. Where the inner lid sheet layer is ofPE peel film, this lid sheet is particularly suitable for use with abase sheet having PVC as its inner base sheet layer.

In a further aspect, the optional first intermediate layer of polymericmaterial comprises the optional first intermediate layer of polymericmaterial comprises cross-laminated high density polyethylene (HDPE) andthe inner lid sheet layer of polymeric material comprises a peel film(e.g. a polyethylene (PE) peel film, a polyvinyl chloride (PVC) peelfilm or a polypropylene (PP) peel film). By cross-laminated HDPE it ismeant a material comprising at least two HDPE films cross-laminated toeach other at a suitable cross-lamination angle, wherein thecross-lamination angle is typically from 30 to 600, particularly 450.The cross-laminated HDPE is typically of thickness from 30 to 100micron, particularly from 50 to 80 micron. The material sold by IllinoisTool Works, Inc. under the trade name Valeron is a suitablecross-laminated HDPE material herein. This lid sheet is particularlysuitable for use with a base sheet having PVC as its inner base sheetlayer.

One suitable drug pack thus, comprises (i) an outer paper lid sheetlayer; bonded via an optional first intermediate layer ofcross-laminated HDPE of thickness from 30 to 100 micron, particularly 50to 80 micron bonded to (ii) an aluminium foil lid sheet layer; bonded to(iii) an inner lid sheet layer of a peel film of thickness from 5 to 50micron, particularly from 10 to 40 micron. Where the inner lid sheetlayer is of PE peel film, this lid sheet is particularly suitable foruse with a base sheet having PVC as its inner base sheet layer.

Various known techniques can be employed to join the lid sheet and basesheet herein and hence to seal the blister pockets. Such methods includeadhesive bonding, radio frequency welding, ultrasonic welding, inductivesealing and hot bar sealing.

The base sheet herein is particularly suitable for forming by ‘coldform’ methods (e.g. one or two step cold forming—advanced formingtechnology (AFT); high pressure cold forming (HPCF)), which areconducted without heating up the material of the base sheet. Such ‘coldform’ methods are of particular utility where the drug or drugformulation for containment within the blister is very sensitive tomoisture, oxygen, other gases and/or flavours. To reduce the influenceof the heat of the sealing process to avoid damages of the filling good,material for the sealing is used with low melting point, e.g.polyethylene, polyethylene/metallocene; Surlyn® as sold by Du Pont. Ifthe packed product does not request a very high barrier to moisture andgases, thermoforming of plastic materials like PVC; polypropylene;PVC/PVDC; PVC/Aclar® or COC-laminates are used to form the blister.

One method for forming a drug pack herein comprises the steps of (a)providing a base sheet having a first mating surface and a lid sheet ahaving a second mating surface, the base sheet including at least oneblister pocket having a periphery region, the blister pocket beingadapted to receive a drug composition; (b) filling the blister pocketwith the pharmaceutical composition (e.g. in an amount from 10 to 3000μg, such as from 25 to 500 μg); (c) bonding the base sheet to the lidsheet to create a primary seal therebetween. The blister pocket can beof any shape for good airflow (e.g. to assist aerosolization of thepowder contained therein), preferably, substantially elongated orsubstantially circular.

In embodiments, the base sheet includes at least a first bondingmaterial disposed on the first mating surface and the lid sheet includesat least a second bonding material disposed on the second matingsurface. In one embodiment, one or both of the first or second bondingmaterials comprises at least one polymeric material. In an additionalembodiment, one or both of the first or second bonding materialcomprises a substance that enables peelable separation e.g. a heat seallacquer, plastic film or coating.

A suitable manufacturing system herein comprises (a) a base transporterfor transporting a base sheet to a filling station, the base sheetincluding at least one blister pocket adapted to receive an inhalabledrug composition, the base sheet further including a first bondingmaterial; (b) a filling apparatus for filling the blister pocket withthe inhalable drug composition; (c) a lid transporter for transporting alid sheet proximate to the filled base sheet, the lid sheet including asecond bonding material; (d) a bonding mechanism for bonding the firstand second bonding materials to create a primary seal therebetween.

In use, the drug pack herein is suitably receivable by a drug dispenserthat comprises a housing for receipt of the drug pack. In one aspect,the drug dispenser has unitary form and the housing is integraltherewith. In another aspect, the drug dispenser is configured toreceive a refill cassette and the housing forms part of that refillcassette.

In embodiments, the interior of the housing is shaped, or alternativelyprovided with specific guiding features, to guide the drug packappropriately into the housing. In particular, the guiding should ensurethat the drug pack is suitably located to interact with internalmechanisms (e.g. indexing and opening mechanisms) of the housing.

In embodiments, the dispenser has an internal mechanism for dispensingthe distinct inhalable drug doses carried by the drug pack foradministration to the patient (e.g. by inhalation). In embodiments, themechanism comprises,

a) receiving means for receiving the drug pack;b) release means for releasing a distinct drug dose from the drug packon receipt thereof by said receiving means;c) an outlet, positioned to be in communication with the drug dosereleasable by said release means;d) indexing means for individually indexing the distinct drug doses ofthe drug pack; and

The mechanism comprises receiving means (e.g. a receiving station) forreceiving the drug pack.

The mechanism further comprises release means for releasing a distinctdrug dose from the drug pack on its receipt by the receiving station.The release means typically comprises means for mechanically peelingapart the blister strip.

An outlet is positioned to be in communication with the distinct drugdoses releasable by said release means. The outlet may have any suitableform. In one aspect, it has the form of a mouthpiece and in another ithas the form of a nozzle for insertion into the nasal cavity of apatient.

The outlet is preferably a single outlet, which communicates with thedistinct drug dose releasable by said release means via a common airchannelling means (e.g. formed as an air-pipe or common manifold). Thepatient may therefore breathe in through a single outlet, and thatbreath be transferred through the common channelling means to thereleased drug dose, thereby enabling its inhalation.

The mechanism also comprises indexing means for individually indexingthe distinct drug doses of the drug pack. Said indexing typicallyhappens in sequential fashion, for example accessing dose portionssequentially arranged along the length of the elongate carrier.

Optionally, the drug dispenser also includes counting means for countingeach time a distinct drug dose of the drug pack is indexed by saidindexing means.

In one aspect, counting means is arranged to count each time a distinctdrug dose of the drug pack is indexed by said indexing means. Inembodiments, the indexing means and counting means engage directly orindirectly (e.g. via a coupling) with each other to enable counting ofeach indexation.

In embodiments, the counting means is provided with (or communicateswith) a display for displaying to the patient the number of distinctdoses left to be taken or the number of doses taken.

In one preferred aspect, the drug dispenser takes the form of adispenser for use with a drug pack having multiple distinct pockets forcontaining inhalable drug doses, wherein said pockets are spaced alongthe length of and defined between two peelable sheets secured to eachother, said dispenser having an internal mechanism for dispensing thedrug doses contained within said drug pack, said mechanism comprising,

a) an opening station for receiving a pocket of the drug pack;b) peeling means positioned to engage a base sheet and a lid sheet of apocket which has been received in said opening station for peeling apartsuch a base sheet and lid sheet, to open such a pocket, said peelingmeans including lid driving means for pulling apart a lid sheet and abase sheet of a pocket that has been received at said opening station;c) an outlet, positioned to be in communication with an opened pocketthrough which a user can access a drug dose from such an opened pocket;d) indexing means for individually indexing the distinct pockets of thedrug pack.

In embodiments, the indexing means comprises a rotatable index wheelhaving recesses therein, said index wheel being engageable with a drugpack herein, in use with said drug dispenser such that said recesseseach receive a respective pocket of the base sheet of a blister stripform drug pack in use with said drug dispenser.

Preferably, the drug dispenser has the general form as described in U.S.Pat. Nos. 5,860,419, 5,873,360 and 5,590,645 in the name of Glaxo GroupLtd, each of which is incorporated herein by reference. An example of adrug dispenser of this type is the well-known Diskus (trade mark)inhaler device as sold by GlaxoSmithKline Plc. The drug dispenser alsomay be employed as described in WO 03/061743 and WO 03/061744, thedisclosures of which are incorporated by reference in their entirety.

According to another aspect of the present invention there is provided adrug dispenser comprising (e.g. loaded with) at least one drug packherein.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIG. 1 shows a perspective view of the form of a drug pack of a formsuitable for use in accord with the present invention;

FIG. 2 shows a top view of the form of a drug pack of a form suitablefor use in accord with the present invention;

FIG. 3 shows a top view of the form of another drug pack of a formsuitable for use in accord with the present invention; and

FIG. 4 shows a cross-sectional side view of the form of a laminate formdrug pack in accord with the present invention; and

FIG. 5 shows a cross-sectional side view of the form of a furtherlaminate form drug pack in accord with the present invention; and

FIG. 6 shows a cross-sectional side view of the form of a furtherlaminate form drug pack in accord with the present invention; and

FIG. 7 shows a cross-sectional side view of the form of a furtherlaminate form drug pack in accord with the present invention; and

FIG. 8 shows a cross-sectional side view of the form of a laminate formlid sheet in accord with the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a drug pack 100 that may be constructed to have a detailedform in accord with the present invention. The drug pack comprises aflexible strip 101 defining a plurality of pockets 103, 105, 107 each ofwhich would contain a portion of a dose of drug which can be inhaled, inthe form of powder.

The strip comprises a base sheet 109 in which blisters are formed todefine the pockets 103, 105, 107 and a lid sheet 111 which ishermetically sealed to the base sheet except in the region of theblisters in such a manner that the lid sheet 111 and the base sheet 109can be peeled apart. The sheets 109, 111 are sealed to one another overtheir whole width except for the leading end portions 113, 115 wherethey are preferably not sealed to one another at all. The lid 111 andbase 109 sheets are formed of a laminate and are suitably adhered to oneanother by heat sealing.

The strip 101 is shown as having elongate pockets 103, 105, and 107 thatrun transversely with respect to the length of the strip 101. This isconvenient in that it enables a large number of pockets 103, 105, 107 tobe provided in a given strip 101 length. The strip 101 may, for example,be provided with sixty or one hundred pockets but it will be understoodthat the strip 101 may have any suitable number of pockets.

Referring now to FIG. 2, there is shown a drug pack in the form of alaminate assembly or blister strip 200 viewed from underneath. Theblister strip has a substantially elongated shape and includes aplurality of blisters 203, 205, 207 formed in the base 209 thereofadapted to receive a pharmaceutical composition, preferably in the formof a dry powder. Each blister 203, 205, 207 has a length l₁ that ispreferably from 1.5 to 15.0 mm, more preferably, from 1.5 to 8.0 mm, andin an actual embodiment is equal to 7.5 mm, measured along its longeraxis, and a width l₂ that is preferably from 1.5 to 10.0 mm, morepreferably, from 1.5 to 8.0 mm, and in an actual embodiment is equal to4.0 mm, measured along its shorter axis.

In the illustrated example of FIG. 2, the blister strip 200 has a widthof 12.5 mm. The thickness of the base 209 is in the range of 75 to 200micron. The thickness of the lid is in the range 40 to 100 micron. Thecombined thickness of the base 209 and lid (not visible) isapproximately 115 to 300 micron. The blisters 203, 205, 207 aretypically at 7.5 mm spacings along the blister strip 200. Each blister203, 205, 207 contains an effective dosage of powder, preferably lessthan 30 mg of powder, more preferably, between 5-25 mg of powder, andmost preferably, approximately 12.5 mg of powder. The powder is aninhalable drug composition comprising at least one drug active.

Suitable materials are employed to construct the base 209 and lid (notvisible). In accord with the invention, the base 209 and/or lid compriselaminate structures having at least one bonding material on at least onemating surface of either the base 209 or lid. The bonding material(s)preferably comprise at least one polymeric material and a heat seallayer (e.g. a heat seal film, a heat seal extrusion coating or a heatseal lacquer such as a vinyllic heat seal lacquer).

Referring now to FIG. 4, there is shown a blister pack 400 herein havinga lid sheet which has a four layer structure and comprises the followingsuccessive layers:

(i) an outer paper lid sheet layer 425; bonded to(ii) a first intermediate lid sheet layer of polymeric material 427;bonded to(iii) an aluminium foil lid sheet layer 429; bonded directly orindirectly to(iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, aheat seal extrusion coating or a heat seal lacquer).

One particular lid sheet variation comprises (i) an outer paper lidsheet layer 425 of weight 25 g/m²; bonded to (ii) a first intermediatelid sheet layer 427 of woven polyamide material of thickness from 50 to120 micron; bonded to (iii) an aluminium foil lid sheet layer 429 ofthickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seallacquer).

Another particular lid sheet variation comprises (i) an outer paper lidsheet layer 425 of weight 20 g/m²; bonded to (ii) a first intermediatelid sheet layer 427 of woven polyamide material of thickness from 50 to100 micron; bonded to (iii) an aluminium foil lid sheet layer 429 ofthickness 20 micron; bonded to (iv) an inner lid sheet heat seal layer430 (e.g. a heat seal film, a heat seal extrusion coating or a heat seallacquer).

Another particular lid sheet comprises (i) an outer paper lid sheetlayer 425 of weight 25 g/m²; bonded using PE extrusion to (ii) a firstintermediate lid sheet layer 427 of spun-PET material of weight 30 g/m²;bonded using PE extrusion to (iii) an aluminium foil lid sheet layer 429of thickness 20 micron; bonded to (iv) an inner lid sheet heat seallayer 430 (e.g. a heat seal film, a heat seal extrusion coating or aheat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheetlayer 425 of weight 25 g/m²; bonded using PE extrusion to (ii) a firstintermediate lid sheet layer 427 of spun-PET material of weight 50 g/m²;bonded using PE extrusion to (iii) an aluminium foil lid sheet layer 429of thickness 20 micron; bonded to (iv) an inner lid sheet heat seallayer 430 (e.g. a heat seal film, a heat seal extrusion coating or aheat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheetlayer 425 of weight 25 g/m²; bonded using extrusion lamination to (ii) afirst intermediate lid sheet layer 427 of spun-PET 488/20 material ofweight 20 g/m²; bonded using two layers of co-extrusion lamination to(iii) an aluminium foil lid sheet layer 429 of thickness 20 micron;bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. a heat sealfilm, a heat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheetlayer 425 of weight 25 μm²; bonded using lacquer lamination to (ii) afirst intermediate lid sheet layer 427 of spun-PET 088/30 material ofweight 30 g/m²; bonded using two layers of lacquer lamination to (iii)an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to(iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, aheat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheetlayer 425 of weight 50 g/m²; bonded using lacquer lamination to (ii) afirst intermediate lid sheet layer 427 of spun-PET 088/30 material ofweight 30 g/m²; bonded using two layers of lacquer lamination to (iii)an aluminium foil lid sheet layer 429 of thickness 20 micron; bonded to(iv) an inner lid sheet heat seal layer 430 (e.g. a heat seal film, aheat seal extrusion coating or a heat seal lacquer).

Another particular lid sheet comprises (i) an outer paper lid sheetlayer 425 of weight 25 g/m²; bonded using PE extrusion to (ii) a firstintermediate lid sheet layer 427 of spun-HDPE material of weight 50g/m²; bonded using PE extrusion to (iii) an aluminium foil lid sheetlayer 429 of thickness 20 micron; bonded to (iv) an inner lid sheet heatseal layer 430 (e.g. a heat seal film, a heat seal extrusion coating ora heat seal lacquer).

One particular lid sheet comprises (i) an outer paper lid sheet layer425 of weight 25 g/m²; bonded to (ii) a first intermediate lid sheetlayer 427 of cross-laminated HDPE material of thickness 70 micron;bonded to (iii) an aluminium foil lid sheet layer 429 of thickness 20micron; bonded to (iv) an inner lid sheet heat seal layer 430 (e.g. aheat seal film, a heat seal extrusion coating or a heat seal lacquer).The material sold by Illinois Tool Works, Inc. under the trade nameValeron is a suitable cross-laminated HDPE material for the layer 427.

The base sheet of the blister pack of FIG. 4 also has a multi-layerstructure and comprises the following successive layers: orientedpolyamide (OPA) 420 adhesively bonded to aluminium foil 422 adhesivelybonded to a base sheet layer 424 of polymeric material of thickness from10 to 100 micron. The blister pack 400 is filled with inhalable drug 414in dry powdered form. In embodiments, the base sheet layer 424 ofpolymeric material meets the requirement that the polymeric material hasa water vapour permeability of less than 0.6 g/(100 inches²) (24 hours)(mil) at 25° C. measured by ASTM E96-635 (E).

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminiumfoil 422; adhesively bonded to 100 micron thickness polyvinyl chloride(PVC) 424.

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminiumfoil 422; adhesively bonded to 60 micron thickness polyvinyl chloride(PVC) 424.

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 20 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminiumfoil 422; adhesively bonded to 60 micron thickness polyvinyl chloride(PVC) 424.

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminiumfoil 422; adhesively bonded to 30 micron thickness polyvinyl chloride(PVC) 424.

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminiumfoil 422; adhesively bonded to 15 micron thickness polyvinyl chloride(PVC) 424.

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 100 μm layer thickness PVC adhesivelybonded to 25 micron layer thickness oriented polyamide (OPA) 420;adhesively bonded to 45 micron thickness aluminium foil 422; adhesivelybonded to 15 micron thickness polyvinyl chloride (PVC) 424.

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminiumfoil 422; adhesively bonded to 30 micron thickness polyvinylidenechloride (PVDC) 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 20 micron thickness orientedpolypropylene 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cast polypropylene424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 20 micron thickness orientedpolypropylene 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cast polypropylene424.

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 60 μm layer thickness polypropylene;adhesively bonded to 25 micron layer thickness oriented polyamide (OPA)420; adhesively bonded to 60 micron thickness aluminium foil 422;adhesively bonded to 25 micron thickness cast polypropylene 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness polypropylene 424,wherein the polypropylene is manufactured by a process in which one ormore metallocene compounds are employed to control side-chaincharacteristics thereof.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 40 micron thickness low densitypolyethylene (LDPE) 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 40 micron thickness high densitypolyethylene (HDPE) 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 20 micron thicknesspolychlorotrifluoroethylene (PCTFE) 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cyclic olefincopolymer (COC) 424.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cyclic olefin polymer(COP) 424.

Any of the particular lid sheet variants described in respect of FIG. 4may be used in combination with any of the particular base sheetvariants described in respect of that same FIG. 4.

As will be appreciated by one having ordinary skill in the art, variousconventional adhesives can be employed to bond the laminate layerswithin the scope of the invention. Such adhesives include, but are notlimited to, cyanoacrylates, acrylics and polyurethanes and resins forextrusion laminating, like EAA, ionomer structures like Surlyn® andBynel® (trade names from Du Pont) and malein-acid-anhydride (MAHresins).

During a typical process for manufacturing a drug pack as shown forexample in FIG. 4, each blister 412 is filled with a pharmaceuticalcomposition 414 and subsequently sealed. The sealing temperature andother parameters of the sealing method may be varied including tooling,dwell time, sealing pressure and speed of sealing. The heat-sealing stepbonds the mating layers (e.g., PVC 424 and heat seal lacquer 430) of thebase and lid to seal each blister 412 and, hence forms a securecontainer for the pharmaceutical composition 414 contained therein.Ideally, the bonding creates a hermetic seal that is formed. As will beappreciated, hermetically sealing each blister 412 to eliminate thepossibility of contamination from the external environment can be animportant aspect of the manufacturing process.

FIGS. 5 and 6 show an alternative drug pack structures herein, in whichthe lid sheet is provided with an inner peelable layer.

Referring now to FIG. 5, there is shown a blister pack 700 herein havinga lid sheet which has a three layer structure and comprises thefollowing successive layers:

(i) an outer paper lid sheet layer 725; bonded to(ii) an aluminium foil lid sheet layer 729; bonded to(iii) an inner lid sheet layer of polymeric material 730.

One particular lid sheet of FIG. 5 comprises (i) an outer paper lidsheet layer 725 of weight 25 g/m²; bonded by polyethylene (PE) extrusionto (ii) an aluminium foil lid sheet layer 729 of thickness 20 micron;bonded to (iii) an inner lid sheet layer 730 of peelable co-extrusioncoating having a weight of 15 g/m².

Another particular lid sheet of FIG. 5 comprises (i) an outer paper lidsheet layer 725 of weight 25 g/m²; bonded to (ii) an aluminium foil lidsheet layer 729 of thickness 38 micron; bonded to (iii) an inner lidsheet layer of polyethylene (PE) peel film of thickness 30 or 40 micron.

The base sheet of the blister pack of FIG. 5 also has a multi-layerstructure and comprises the following successive layers: orientedpolyamide (OPA) 720 of thickness 25 micron adhesively bonded toaluminium foil 722 of thickness 45 micron adhesively bonded to a basesheet layer 724 of PE peel film of thickness 30 micron. The blister pack700 is filled with inhalable drug 714 in dry powdered form.

Referring now to FIG. 6, there is shown a blister pack 800 herein havinga lid sheet which has a three layer structure and comprises thefollowing successive layers:

(i) an outer paper lid sheet layer 825; bonded to(ii) an intermediate layer of polymeric material 827; bonded to(iii) an aluminium foil lid sheet layer 829; bonded to(iv) an inner lid sheet layer of polymeric material 830.

One particular drug pack of FIG. 6 thus, comprises (i) an outer paperlid sheet layer 825 of weight 25 g/m²; bonded to (ii) intermediate layer827 of PET of thickness 12 micron bonded to (iii) an aluminium foil lidsheet layer 829 of thickness 20 micron; bonded to (iv) an inner lidsheet layer 830 of PVC film of thickness 15 or 30 micron. This lid sheetis particularly suitable for use with a base sheet having heat seallacquer as its inner base sheet layer.

Thus, the base sheet of the blister pack of FIG. 6 also has amulti-layer structure and comprises the following successive layers:oriented polyamide (OPA) 820 of thickness 25 micron adhesively bonded toaluminium foil 822 of thickness 60 micron adhesively bonded to a basesheet layer 824 of heat seal lacquer. The blister pack 800 is filledwith inhalable drug 814 in dry powdered form.

Referring now to FIG. 7, there is shown a blister pack 900 herein havinga lid sheet which has a three layer structure and comprises thefollowing successive layers:

(i) an outer paper lid sheet layer 925; bonded to(ii) an intermediate layer of polymeric material 927; bonded to(iii) an aluminium foil lid sheet layer 929; bonded to(iv) an inner lid sheet layer of polymeric material 930.

One particular drug pack of FIG. 7 thus, comprises (i) an outer paperlid sheet layer 925 of weight 25 g/m²; bonded by extrusion lamination to(ii) intermediate layer 927 of spun-PET 488/20 of thickness 20 micronbonded by two co-extrusion lamination layers to (iii) an aluminium foillid sheet layer 929 of thickness 20 micron; bonded by lacquer laminationto (iv) an inner lid sheet layer 930 of PE peel film of thickness 30micron.

Another particular drug pack of FIG. 7 thus, comprises (i) an outerpaper lid sheet layer 925 of weight 25 g/m²; bonded by extrusionlamination to (ii) intermediate layer 927 of spun-PET 488/30 ofthickness 30 micron bonded by two co-extrusion lamination layers to(iii) an aluminium foil lid sheet layer 929 of thickness 20 micron;bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PEpeel film of thickness 30 micron.

A further particular drug pack of FIG. 7 thus, comprises (i) an outerpaper lid sheet layer 925 of weight 25 g/m²; bonded by extrusionlamination to (ii) intermediate layer 927 of spun-PET 088/30 ofthickness 30 micron bonded by two co-extrusion lamination layers to(iii) an aluminium foil lid sheet layer 929 of thickness 20 micron;bonded by lacquer lamination to (iv) an inner lid sheet layer 930 of PEpeel film of thickness 30 micron.

A further particular drug pack of FIG. 7 thus, comprises (i) an outerpaper lid sheet layer 925 of weight 25 g/m²; bonded by lacquerlamination to (ii) intermediate layer 927 of spun-PET 088/30 ofthickness 30 micron bonded by lacquer lamination to (iii) an aluminiumfoil lid sheet layer 929 of thickness 20 micron; bonded by lacquerlamination to (iv) an inner lid sheet layer 930 of PE peel film ofthickness 30 micron.

A further particular drug pack of FIG. 7 thus, comprises (i) an outerpaper lid sheet layer 925 of weight 50 g/m²; bonded by lacquerlamination to (ii) intermediate layer 927 of spun-PET 088/30 ofthickness 30 micron bonded by lacquer lamination to (iii) an aluminiumfoil lid sheet layer 929 of thickness 20 micron; bonded by lacquerlamination to (iv) an inner lid sheet layer 930 of PE peel film ofthickness 30 micron.

A further drug pack of FIG. 7 thus, comprises (i) an outer paper lidsheet layer 925 of weight 25 g/m²; bonded by lacquer lamination to (ii)intermediate layer 927 of cross-laminated HDPE of thickness 60 micronbonded by lacquer lamination to (iii) an aluminium foil lid sheet layer929 of thickness 20 micron; bonded by lacquer lamination to (iv) aninner lid sheet layer 930 of PE peel film of thickness 30 micron. Thematerial sold by Illinois Tool Works, Inc. under the trade name Valeronis a suitable cross-laminated HDPE material.

A further drug pack of FIG. 7 thus, comprises (i) an outer paper lidsheet layer 925 of weight 50 g/m²; bonded by lacquer lamination to (ii)intermediate layer 927 of cross-laminated HDPE of thickness 60 micronbonded by lacquer lamination to (iii) an aluminium foil lid sheet layer929 of thickness 20 micron; bonded by lacquer lamination to (iv) aninner lid sheet layer 930 of PE peel film of thickness 30 micron. Thematerial sold by Illinois Tool Works, Inc. under the trade name Valeronis a suitable cross-laminated HDPE material.

A further drug pack of FIG. 7 thus, comprises (i) an outer paper lidsheet layer 925 of weight 25 g/m²; bonded by lacquer lamination to (ii)intermediate layer 927 of cross-laminated HDPE of thickness 60 micronbonded by lacquer lamination to (iii) an aluminium foil lid sheet layer929 of thickness 20 micron; bonded by lacquer lamination to (iv) aninner lid sheet layer 930 of PVC peel film of thickness 30 micron. Thematerial sold by Illinois Tool Works, Inc. under the trade name Valeronis a suitable cross-laminated HDPE material.

A further drug pack of FIG. 7 thus, comprises (i) an outer paper lidsheet layer 925 of weight 50 g/m²; bonded by lacquer lamination to (ii)intermediate layer 927 of cross-laminated HDPE of thickness 60 micronbonded by lacquer lamination to (iii) an aluminium foil lid sheet layer929 of thickness 20 micron; bonded by lacquer lamination to (iv) aninner lid sheet layer 930 of PVC peel film of thickness 30 micron. Thematerial sold by Illinois Tool Works, Inc. under the trade name Valeronis a suitable cross-laminated HDPE material.

Thus, the base sheet of the blister pack of FIG. 7 also has amulti-layer structure and comprises the following successive layers:oriented polyamide (OPA) 920 of thickness 25 micron adhesively bonded toaluminium foil 922 of thickness 60 micron adhesively bonded to a basesheet layer 924 of thickness of from 15 to 100 micron PVC. The blisterpack 900 is filled with inhalable drug 914 in dry powdered form.

In further embodiments, the respective lid sheets of FIGS. 5 to 7 hereinmay also be employed with any of the base sheets of FIG. 4 herein.

Various bonding schemes and patterns may be employed to bond and sealblister strip packs such as shown in FIGS. 4 to 7. Illustrative are thebonding schemes and patterns shown in FIGS. 2 and 3.

Referring now to FIG. 2, there is shown a bonding scheme that employssubstantially uniformly distributed heat across at least one surface ofthe blister strip 200 to create discrete bond areas of the mating base209 and lid surfaces. Although various bond patterns can be formed bythis bonding scheme (e.g., zig-zag, dot, checkered, etc.), a checkeredgrid 216 pattern is employed in this example.

As illustrated in FIG. 2, the grid 216 provides a restricted, tortuouspath (designated generally by Arrow M) for the ingress of contaminantsand/or moisture into the blisters 203, 205, 207.

Referring now to FIG. 3, there is shown a further bonding scheme thatemploys substantially uniformly distributed heat across at least onesurface of the blister strip 300 to create discrete bond areas of themating base 309 and lid surfaces. A knurled form bond pattern 316 isemployed in this example. The knurling 316 provides a restricted,tortuous path (designated generally by Arrow M) for the ingress ofcontaminants and/or moisture into the blisters 303, 305, 307.

FIG. 8 shows a lid sheet (‘cover foil’) 1011 suitable for use in ablister pack herein (not represented) and having the following layerstructure from outside inwards:

Layer A 1025 for example, comprised of overprinted satined paper ofweight 30 g/m²;

Laminating aid 1026;

Layer B 1027 for example, comprised of a non-woven material made fromHDPE with a weight of 60 g/m²;

Laminating aid 1028;

Layer C 1029 for example, comprised of 25 μm thick aluminium foil; andLayer D 1030 for example, comprised of heat seal lacquer

The lid sheet of the drug packs herein is designed to provide enhancedtear resistance and tear propagation resistance. Tear resistance is ameasure of resistance of the lid sheet to initial tearing thereof and isgenerally related to tensile strength and puncture resistance propertiesof at least one layer of the lid sheet, generally a polymeric materiallayer. Tear propagation resistance is a measure of the resistance of thelid sheet to tear further once an initial tear (or nick or cut orsimilar) has been experienced by the lid sheet and in existing lidsheets is generally related to the properties of the paper and aluminiumfoil lid sheet layers. Tear resistance can be measured in the laboratoryby the ASTM method having the reference number ASTM D1004. Tearpropagation resistance can be measured in the laboratory by a methodcalled the Elmendorf test (DIN 53128 or EN21974).

The lid sheet of the drug packs herein suitably has a tear resistance ofgreater than 20N and a tear propagation resistance of greater than 2.5N.

The drug pack and related drug dispenser device of the invention issuitable for dispensing drug products particularly for the treatment ofrespiratory disorders such as asthma and chronic obstructive pulmonarydisease (COPD), bronchitis and chest infections. Other applications arealso envisaged.

Appropriate drugs may thus be selected from, for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate(e.g. as the sodium salt), ketotifen or nedocromil (e.g. as the sodiumsalt); antiinfectives e.g., cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.,methapyrilene; anti-inflammatories, e.g., beclomethasone (e.g. as thedipropionate ester), fluticasone (e.g. as the propionate ester),flunisolide, budesonide, rofleponide, mometasone e.g. as the furoateester), ciclesonide, triamcinolone (e.g. as the acetonide) or 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl)ester,(6α,11β,16α,17α)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl2-furoate,and(6α,11β,16α,17α)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl4-methyl-1,3-thiazole-5-carboxylate; antitussives, e.g., noscapine;bronchodilators, e.g.,3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide,3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide,4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol,4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol,N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide,N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine,5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,5-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-2(1H)-quinolinone,albuterol (e.g. as free base or sulphate), salmeterol (e.g. asxinafoate), ephedrine, adrenaline, fenoterol (e.g. as hydrobromide),formoterol (e.g. as fumarate), isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol (e.g. as acetate),reproterol (e.g. as hydrochloride), rimiterol, terbutaline (e.g. assulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoicacid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride;anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium,atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines, e.g., aminophylline, choline theophyllinate,lysine theophyllinate ortheophylline; therapeutic proteins and peptides,e.g., insulin or glucagon; vaccines, diagnostics, and gene therapies. Itwill be clear to a person skilled in the art that, where appropriate,the drugs may be used in the form of salts, (e.g., as alkali metal oramine salts or as acid addition salts) or as esters (e.g., lower alkylesters) or as solvates (e.g., hydrates) to optimise the activity and/orstability of the drug.

The drug product may in aspects, be a mono-therapy (i.e. single activedrug containing) product or it may be a combination therapy (i.e. pluralactive drugs containing) product.

Suitable drugs or drug components of a combination therapy product aretypically selected from the group consisting of anti-inflammatory agents(for example a corticosteroid or an NSAID), anticholinergic agents (forexample, an M₁, M₂, M₁/M₂ or M₃ receptor antagonist), otherβ₂-adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic oran antiviral), and antihistamines. All suitable combinations areenvisaged.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17β-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.chemokine antagonists) or inhibitors of cytokine synthesis. Suitableother β₂-adrenoreceptor agonists include salmeterol (e.g. as thexinafoate), salbutamol (e.g. as the sulphate or the free base),formoterol (e.g. as the fumarate), fenoterol or terbutaline and saltsthereof.

Suitable phosphodiesterase 4 (PDE4) inhibitors include compounds thatare known to inhibit the PDE4 enzyme or which are discovered to act as aPDE4 inhibitor, and which are only PDE4 inhibitors, not compounds whichinhibit other members of the PDE family as well as PDE4. Generally it ispreferred to use a PDE4 inhibitor which has an IC₅₀ ratio of about 0.1or greater as regards the IC₅₀ for the PDE4 catalytic form which bindsrolipram with a high affinity divided by the IC₅₀ for the form whichbinds rolipram with a low affinity. For the purposes of this disclosure,the cAMP catalytic site which binds R and S rolipram with a low affinityis denominated the “low affinity” binding site (LPDE 4) and the otherform of this catalytic site which binds rolipram with a high affinity isdenominated the “high affinity” binding site (HPDE 4). This term “HPDE4”should not be confused with the term “hPDE4” which is used to denotehuman PDE4.

A method for determining IC₅₀s ratios is set out in U.S. Pat. No.5,998,428 which is incorporated herein in full by reference as thoughset out herein. See also PCT application WO 00/51599 for anotherdescription of said assay.

Suitable PDE4 inhibitors include those compounds which have a salutarytherapeutic ratio, i.e., compounds which preferentially inhibit cAMPcatalytic activity where the enzyme is in the form that binds rolipramwith a low affinity, thereby reducing the side effects which apparentlyare linked to inhibiting the form which binds rolipram with a highaffinity. Another way to state this is that the preferred compounds willhave an IC₅₀ ratio of about 0.1 or greater as regards the IC₅₀ for thePDE4 catalytic form which binds rolipram with a high affinity divided bythe IC₅₀ for the form which binds rolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM[³H]-cAMPas the substrate.

Most suitable are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other suitable drug compounds include:cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) disclosed in U.S. Pat. No. 5,552,438 andits salts, esters, pro-drugs or physical forms; AWD-12-281 from elbion(Hofgen, N. et al. 15th EFMC Int Symp Med Chem (September 6-10,Edinburgh) 1998, Abst P. 98; CAS reference No. 247584020-9); a9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 fromChiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitoridentified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl.28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine, (−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compounds,which are antagonists of the M₁ and M₂ receptors. Exemplary compoundsinclude the alkaloids of the belladonna plants as illustrated by thelikes of atropine, scopolamine, homatropine, hyoscyamine; thesecompounds are normally administered as a salt, being tertiary amines.

Particularly suitable anticholinergics include ipratropium (e.g. as thebromide), sold under the name Atrovent, oxitropium (e.g. as the bromide)and tiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. Examples include ethanolamines, ethylenediamines, andalkylamines. In addition, other first generation antihistamines includethose which can be characterized as based on piperizine andphenothiazines. Second generation antagonists, which are non-sedating,have a similar structure-activity relationship in that they retain thecore ethylene group (the alkylamines) or mimic the tertiary amine groupwith piperizine or piperidine. Exemplary antagonists are as follows:

Ethanolamines: carbinoxamine maleate, clemastine fumarate,diphenylhydramine hydrochloride, and dimenhydrinate.Ethylenediamines: pyrilamine amleate, tripelennamine HCl, andtripelennamine citrate.Alkylamines: chlropheniramine and its salts such as the maleate salt,and acrivastine.Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,cyclizine lactate, meclizine HCl, and cetirizine HCl.Piperidines: Astemizole, levocabastine HCl, loratadine or itsdescarboethoxy analogue, and terfenadine and fexofenadine hydrochlorideor another pharmaceutically acceptable salt.Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

Particularly suitable anti-histamines include methapyrilene andloratadine.

In respect of combination products, co-formulation compatibility isgenerally determined on an experimental basis by known methods and maydepend on chosen type of drug dispenser action.

The drug components of a combination product are suitably selected fromthe group consisting of anti-inflammatory agents (for example acorticosteroid or an NSAID), anticholinergic agents (for example, an M₁,M₂, M₁/M₂ or M₃ receptor antagonist), other β₂-adrenoreceptor agonists,antiinfective agents (e.g. an antibiotic or an antiviral), andantihistamines. All suitable combinations are envisaged.

In embodiments, the co-formulation compatible components comprise aβ₂-adrenoreceptor agonist and a corticosteroid; and the co-formulationincompatible component comprises a PDE-4 inhibitor, an anti-cholinergicor a mixture thereof. The β₂-adrenoreceptor agonists may for example besalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (eg as the fumarate salt).The corticosteroid may for example, be a beclomethasone ester (e.g., thedipropionate) or a fluticasone ester (e.g., the propionate) orbudesonide.

In one example, the co-formulation compatible components comprisefluticasone propionate and salmeterol, or a salt thereof (particularlythe xinafoate salt) and the co-formulation incompatible componentcomprises a PDE-4 inhibitor, an anti-cholinergic (e.g. ipratropiumbromide or tiotropium bromide) or a mixture thereof.

In another example, the co-formulation compatible components comprisebudesonide and formoterol (e.g. as the fumarate salt) and theco-formulation incompatible component comprises a PDE-4 inhibitor, ananti-cholinergic (e.g. ipratropium bromide or tiotropium bromide) or amixture thereof.

Generally, powdered drug particles suitable for delivery to thebronchial or alveolar region of the lung have an aerodynamic diameter ofless than 10 micrometers, preferably less than 6 micrometers. Othersized particles may be used if delivery to other portions of therespiratory tract is desired, such as the nasal cavity, mouth or throat.The drug may be delivered as pure drug, but more appropriately, it ispreferred that drugs are delivered together with excipients (carriers)which are suitable for inhalation. Suitable excipients include organicexcipients such as polysaccharides (i.e. starch, cellulose and thelike), lactose, glucose, mannitol, amino acids, and maltodextrins, andinorganic excipients such as calcium carbonate or sodium chloride.Lactose is a preferred excipient.

Particles of powdered drug and/or excipient may be produced byconventional techniques, for example by micronisation, milling orsieving. Additionally, drug and/or excipient powders may be engineeredwith particular densities, size ranges, or characteristics. Particlesmay comprise active agents, surfactants, wall forming materials, orother components considered desirable by those of ordinary skill.

The excipient may be included with the drug via well-known methods, suchas by admixing, co-precipitating and the like. Blends of excipients anddrugs are typically formulated to allow the precise metering anddispersion of the blend into doses. A standard blend, for example,contains 13000 micrograms lactose mixed with 50 micrograms drug,yielding an excipient to drug ratio of 260:1. Dosage blends withexcipient to drug ratios of from 100:1 to 1:1 may be used. At very lowratios of excipient to drug, however, the drug dose reproducibility maybecome more variable.

The drug pack and dispenser device of the invention is in one aspectsuitable for dispensing drug for the treatment of respiratory disorderssuch as disorders of the lungs and bronchial tracts including asthma andchronic obstructive pulmonary disorder (COPD). In another aspect, theinvention is suitable for dispensing drug for the treatment of acondition requiring treatment by the systemic circulation of drug, forexample migraine, diabetes, pain relief e.g. inhaled morphine.

Accordingly, there is provided the use of a drug pack and dispenserdevice according to the invention for the treatment of a respiratorydisorder, such as asthma and COPD. Alternatively, the present inventionprovides a method of treating a respiratory disorder such as, forexample, asthma and COPD, which comprises administration by inhalationof an effective amount of drug product as herein described from a drugpack or dispenser device of the present invention.

The amount of any particular drug compound or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof which is required to achieve a therapeutic effect will, ofcourse, vary with the particular compound, the route of administration,the subject under treatment, and the particular disorder or diseasebeing treated. The drugs for treatment of respiratory disorders hereinmay for example, be administered by inhalation at a dose of from 0.0005mg to 10 mg, preferably 0.005 mg to 0.5 mg. The dose range for adulthumans is generally from 0.0005 mg to 100 mg per day and preferably 0.01mg to 1 mg per day.

It will be understood that the present disclosure is for the purpose ofillustration only and the invention extends to modifications, variationsand improvements thereto.

The application of which this description and claims form part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described therein. They may take the form ofproduct, method or use claims and may include, by way of example andwithout limitation, one or more of the following claims:

1. A lid sheet for use in a blister form pack for packaging ofpharmaceutical and medical products, wherein said lid sheet is alaminate comprising four layers A, B, C and D with the layer sequenceA-B-C-D and the layers comprising as follows: (Layer A) a layer Amaterial selected from the group consisting of cellulose material;aluminium foil; plastic film with a temperature resistance of at least 1second at 220° C.; lacquer with a temperature resistance of at least 1second at 220° C.; and anti-adhesive coating; (Layer B) a layer Bmaterial selected from the group consisting of: (1) at least twonon-orientated, mono-orientated or biaxially orientated plastic filmsdisplaced at an angle and bonded by means of lamination or hotcalendaring or plastic coating with a net-like structure; (2)(non-wovenmaterial made from a plastic polymer; (3) at least one fibre or aplastic film possessing a net-like web; (4) a foil comprising a materialselected from the group consisting of Polysulfone,Polyethylenenaphthalate PEN, polyphenylsulfone (PPSU), polyimide (PI);Polyetherimide (PEI) and Tetrafluoroethylene/ethylene; and (5) amultilayer foil consisting of at least two of the aforementionedmaterials; (Layer C) aluminium foil; and (Layer D) a heat seal layer. 2.A lid sheet according to claim 1, wherein layers A and B and layers Band C are bonded using a laminating aid to achieve a bond strength of atleast 2N/15 mm.
 3. A lid sheet according to claim 1, wherein the paperof layer A is untreated, coated or satined and has a weight of 15 to 100g/m2.
 4. A lid sheet according to claim 1, wherein the aluminium foil oflayer A has a thickness of 6 to 60 μm.
 5. A lid sheet according to claim1, wherein the temperature resistant plastic film of layer A has athickness of 7 to 25 μm.
 6. A lid sheet according to claim 1, whereinthe temperature resistant plastic film of layer A is selected from thegroup consisting of Polyethylenterephthalate (PET), orientated Polyamide(OPA), Polysulfone (PSU), Polyphenylsulfone (PPSU), Polyaryletherketone(PEEK), Polyimide (PI), Polyetherimide (PEI),Tetrafluorethylene/ethylene, and any combination thereof, and whereinsaid temperature resistant plastic film of layer A has a thickness of 7to 25 μm.
 7. A lid sheet according to claim 1, wherein the plastic filmsof layer B are individually selected from the group consisting ofPolyethylene (PE), in particular VLDPE, LLDPE, LMDPE, LDPE or HDPE,Polypropylene (PP), Polyester, Polyamide (PA), Polystyrene (PS),Polycarbonate (PC), halogen-containing plastics, in particularPolyvinychloride (PVC), Polyvinylidenchloride (PVDC) orPolychlorotrifluoroethylene (PCTFE), Poly-Acrylic-Nitrile (PAN),Tetrafluoroethylene and any combination thereof and wherein said plasticfilms of layer B has a thickness of 8 to 200 μm.
 8. A lid sheetaccording to claim 1, wherein the plastic coating of the net-likestructure of layer B is selected from the group consisting ofPolyethylene (PE), Polypropylene (PP), Polyester, Polyamide (PA),halogen-containing plastics, Tetrafluorethylene/ethylene, protein(satin), and any combination thereof, and wherein said plastics coatinghas a surface weight of 30 to 150 g/m².
 9. A lid sheet according toclaim 1, wherein the non-woven fibre of layer B is selected from thegroup consisting of HDPE, Polyester, PET/Polybutylenterephthalate (PBT)with Polyamide 6 or Polyamide 6.6, Polyester with polyolefines,Tetrafluoroethylene/ethylene, and any combination thereof, and whereinthe non-woven fibre of layer B has a weight of 10 to 120 g/m².
 10. A lidsheet according to claim 1, wherein the foil consisting of at least onefibre or a plastic film of layer B possessing a net-like web comprises amaterial selected from the group consisting of Polyethylene (PE),Polyprolylene (PP), Polyester, Polyamide (PA), Polystyrene (PS),Polycarbonate (PC), halogen-containing plastics, Poly-Acrylic-Nitrile(PAN), Tetrafluoroethylene/ethylene, and any combination thereof andwherein the foil has a thickness of 8 to 200 μm.
 11. A lid sheetaccording to claim 1, wherein the individual films of the multiplayerfoil of layer B are independently selected from the group consisting ofPolyethylene (PE), Polypropylene (PP), Polyester, Polyamide (PA),Polystyrene (PS), Polycarbonate (PC), halogen-containing plastics,Poly-Acrylic-Nitrile (PAN), Tetrafluorethylene/ethylene, and anycombination thereof and wherein the individual films have a thickness of8 to 200 μm.
 12. A lid sheet according to claim 1, wherein the aluminiumfoil of layer C has a thickness of 7 to 60 μm.
 13. A blister form packfor packaging of pharmaceutical and medical products comprising (a) abase sheet in which blisters are formed to define pockets therein; and(b) a lid sheet according to claim 1, which is sealable to the basesheet except in the region of the blisters and mechanically peelablefrom the base sheet.
 14. A blister form drug pack according to claim 13comprising (a) a base sheet in which blisters are formed to definepockets therein for the containment of inhalable drug; (b) a lid sheetwhich is sealable to the base sheet except in the region of the blistersand mechanically peelable from the base sheet to enable release of saidinhalable drug, wherein said lid sheet has a laminate structurecomprising at least the following successive layers: (Layer A) an outerlid sheet layer of cellulose material; bonded to (Layer B) a firstintermediate lid sheet layer of comprising of a layer B material; bondeddirectly or indirectly to (Layer C) an aluminium foil lid sheet layer;bonded directly or indirectly to (Layer D) an inner lid sheet heat seallayer.
 15. A drug pack according to claim 14 in the form of an elongateblister strip.
 16. A drug pack according to claim 14, wherein the firstintermediate lid sheet layer comprises woven polyamide.
 17. A drug packaccording to claim 16, wherein the woven polyamide layer has a thicknessfrom 50 to 100 micron.
 18. A drug pack according to claim 17, whereinbonding of the woven polyamide layer to its adjacent layers is by way ofadhesive lamination.
 19. A drug pack according to claim 17, whereinbonding of the woven polyamide layer to its adjacent layers is by way ofextrusion lamination.
 20. A drug pack according to claim 14, wherein thefirst intermediate lid sheet layer comprises spun-PET.
 21. A drug packaccording to claim 20, wherein the spun-PET is of weight from 10 to 250g/m².
 22. A drug pack according to claim 21, wherein bonding of thespun-PET layer to its adjacent layers is by way of a laminationtechnique selected from the group consisting of extrusion lamination,co-extrusion lamination and lacquer lamination.
 23. A drug packaccording to claim 22, wherein bonding of the spun-PET layer to itsadjacent layers is by way of polyethylene (PE) extrusion lamination. 24.A drug pack according to claim 14, wherein the first intermediate lidsheet layer comprises spun-HDPE.
 25. A drug pack according to claim 24,wherein the spun-HDPE is of weight from 10 to 80 g/m².
 26. A drug packaccording to claim 24, wherein bonding of the spun-HDPE layer to itsadjacent layers is by way of extrusion lamination.
 27. A drug packaccording to claim 26, wherein bonding of the spun-HDPE layer to itsadjacent layers is by way of polyethylene (PE) extrusion.
 28. A drugpack according to claim 14, wherein the first intermediate lid sheetlayer comprises cross-laminated HDPE.
 29. A drug pack according to claim28, wherein said cross-laminated HDPE comprises at least two HDPE filmscross-laminated to each other at a cross-lamination angle of from 30 to60°.
 30. A drug pack according to claim 28, wherein the cross-laminatedHDPE layer has a thickness from 30 to 100 micron, particularly from 50to 80 micron.
 31. A drug pack according to claim 14, wherein the firstintermediate lid sheet layer comprises cross-laminated PET.
 32. A drugpack according to claim 31, wherein said cross-laminated PET comprisesat least two PET films cross-laminated to each other at across-lamination angle of from 30 to 60°.
 33. A drug pack according toclaim 31, wherein the cross-laminated PET layer has a thickness from 30to 100 micron.
 34. A drug pack according to claim 14, wherein the outerpaper lid sheet layer comprises paper of grade from 10 to 50 g/m².
 35. Adrug pack according to claim 14, wherein the thickness of the aluminiumfoil lid sheet layer is from 10 to 60 micron.
 36. A blister form drugpack comprising (a) a base sheet in which blisters are formed to definepockets therein for the containment of inhalable drug; (b) a lid sheetwhich is sealable to the base sheet except in the region of the blistersand mechanically peelable from the base sheet to enable release of saidinhalable drug, wherein said lid sheet has a laminate structurecomprising at least the following successive layers: (i) an outer lidsheet layer of cellulose material; bonded directly or via an optionalfirst intermediate layer of polymeric material to (ii) an aluminium foillid sheet layer; bonded to (iii) an inner lid sheet layer of polymericmaterial.
 37. A drug pack according to claim 36 in the form of anelongate blister strip.
 38. A drug pack according to claim 36, whereinsaid optional first intermediate layer of polymeric material comprisespolyethylene (PE) extrusion layer and the inner lid sheet layer ofpolymeric material comprises a peelable co-extrusion coating.
 39. A drugpack according to claim 38, wherein the peelable co-extrusion coatinglayer has a weight of from 5 to 50 g/m².
 40. A drug pack according toclaim 36, wherein no optional first intermediate layer of polymericmaterial is present and the inner lid sheet layer of polymeric materialcomprises a peel film.
 41. A drug pack according to claim 40, whereinsaid peel film is selected from the group consisting of a polyethylene(PE) peel film, a polyvinyl chloride (PVC) peel film and a polypropylene(PP) peel film.
 42. A drug pack according to claim 40, wherein the peelfilm is particularly suitable for peelable sealing to an inner basesheet layer comprising polyvinyl chloride (PVC) or polyethylene (PE).43. A drug pack according to claim 40, wherein the peel film layer is ofthickness from 10 to 80 micron.
 44. A drug pack according to claim 36,wherein the optional first intermediate layer of polymeric materialcomprises poly (ethylene terephthalate) (PET) and the inner lid sheetlayer of polymeric material comprises polyvinyl chloride (PVC).
 45. Adrug pack according to claim 44, wherein the PET layer is of thicknessfrom 5 to 30 micron; and the PVC layer is of thickness from 5 to 50micron.
 46. A drug pack according to claim 36, wherein the optionalfirst intermediate layer of polymeric material comprises spun poly(ethylene terephthalate) (spun-PET) and the inner lid sheet layer ofpolymeric material comprises a peel film.
 47. A drug pack according toclaim 46, wherein said peel film is selected from the group consistingof a polyethylene (PE) peel film, a polyvinyl chloride (PVC) peel filmand a polypropylene (PP) peel film.
 48. A drug pack according to claim46, wherein the peel film is particularly suitable for peelable sealingto an inner base sheet layer comprising polyvinyl chloride (PVC) orpolyethylene (PE).
 49. A drug pack according to claim 46, wherein thespun-PET layer is of thickness from 10 to 60 micron; and the peel filmlayer is of thickness from 5 to 50 micron.
 50. A drug pack according toclaim 36, wherein the optional first intermediate layer of polymericmaterial comprises cross-laminated high density polyethylene (HDPE) andthe inner lid sheet layer of polymeric material comprises a peel film.51. A drug pack according to claim 50, wherein said cross-laminated HDPEcomprises at least two HDPE films cross-laminated to each other at across-lamination angle of from 30 to 60°.
 52. A drug pack according toclaim 50, wherein said cross-laminated HDPE layer is of thickness from30 to 100 micron; and the peel film layer is of thickness from 5 to 50micron.
 53. A drug pack according to claim 50, wherein said peel film isselected from the group consisting of a polyethylene (PE) peel film, apolyvinyl chloride (PVC) peel film and a polypropylene (PP) peel film.54. A drug pack according to claim 50, wherein the peel film isparticularly suitable for peelable sealing to an inner base sheet layercomprising polyvinyl chloride (PVC) or polyethylene (PE).
 55. A drugpack according to claim 36, wherein bonding of the optional firstintermediate layer of polymeric material to its adjacent layers is byway of a lamination technique selected from the group consisting ofextrusion lamination, co-extrusion lamination and lacquer lamination.56. A drug pack according to claim 36, wherein the outer paper lid sheetlayer comprises paper of grade from 10 to 80 g/m².
 57. A drug packaccording to claim 36, wherein the thickness of the aluminium foil lidsheet layer is from 10 to 60 micron.
 58. A drug pack according to claim14, wherein the base sheet herein comprises (i) a first base sheet layerof aluminium foil; and (ii) a second base sheet layer of polymericmaterial of thickness from 10 to 150 micron.
 59. A drug pack accordingto claim 58, wherein the first base sheet layer of aluminium foiltypically has a thickness of from 15 to 120 micron.
 60. A drug packaccording to claim 58, wherein the second base sheet layer of polymericmaterial has a thickness of from 10 to 120 micron.
 61. A drug packaccording to claim 58, wherein the second base sheet layer comprises apolymeric material of water vapour permeability of less than 0.6 g/(100inches²) (24 hours) (mil) at 25° C.
 62. A drug pack according to claim61, wherein the second base sheet layer comprises a material selectedfrom the group consisting of polyvinyl chloride (PVC); polypropylene;polyethylene; polyvinylidene chloride (PVDC);polychlorotrifluoroethylene (PCTFE); cyclic olefin copolymer (COC); andcyclic olefin polymer (COP).
 63. A drug pack according to claim 58,wherein the first base sheet layer of aluminium foil is provided with anouter base sheet layer of a polymeric material.
 64. A drug packaccording to claim 63, wherein, said outer layer base sheet layercomprises oriented polyamide (OPA).
 65. A drug pack according to claim40, wherein the base sheet has a PE peel film provided as an inner basesheet layer.
 66. A drug pack according to claim 44, wherein the basesheet is provided with an inner base sheet layer comprising heat seallacquer.
 67. A drug pack according to claim 46, wherein the base sheetis provided with an inner base sheet layer comprising polyvinyl chloride(PVC).
 68. A blister form drug pack according to claim 46, wherein oneor more of said blisters of the pack contain inhalable drug in drypowder form.
 69. A blister form drug pack according to claim 68, whereinsaid inhalable drug comprises one or more drug actives selected from thegroup consisting of anti-inflammatory agents, anticholinergic agents,other β₂-adrenoreceptor agonists, antiinfective agents, antihistaminesand any mixtures thereof.
 70. A blister form drug pack according toclaim 69, wherein said anti-inflammatory agents are selected from thegroup consisting of corticosteroids, NSAIDs and any mixtures thereof.71. A blister form drug pack according to claim 69, wherein saidcorticosteroids are selected from the group consisting of methylprednisolone, prednisolone, dexamethasone, fluticasone propionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl)ester, beclomethasone esters,flunisolide, mometasone esters, triamcinolone acetonide, rofleponide,ciclesonide, butixocort propionate, RPR-106541, and ST-126 and anymixtures thereof.
 72. A blister form drug pack according to claim 69,wherein said NSAIDs are selected from the group consisting of sodiumcromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors,leukotriene antagonists, inhibitors of leukotriene synthesis, iNOSinhibitors, tryptase and elastase inhibitors, beta-2 integrinantagonists, adenosine receptor agonists or antagonists, cytokineantagonists, inhibitors of cytokine synthesis and any mixtures thereof.73. A drug dispenser device comprising a housing; and within saidhousing an elongate form blister form drug pack according to claim 68,wherein the dispenser device includes an internal mechanism fordispensing the inhalable drug from the pockets of the drug pack, saidmechanism comprising, a) an opening station for receiving a pocket ofthe drug pack; b) peeling means positioned to engage the base sheet andthe lid sheet of a pocket which has been received in said openingstation for peeling apart such base sheet and lid sheet, to open such apocket, said peeling means including lid driving means for pulling apartthe lid sheet and the base sheet of a pocket that has been received atsaid opening station; c) an outlet, positioned to be in communicationwith an opened pocket through which a user can access a drug dose fromsuch an opened pocket; d) indexing means for individually indexing thedistinct pockets of the drug pack.
 74. (canceled)
 75. A blister formpack for packaging of packaging of products, the pack comprising (a) abase sheet in which blisters are formed to define pockets therein; and(b) a lid sheet according to any of claims 1 to 12, which is sealable tothe base sheet except in the region of the blisters and mechanicallypeelable from the base sheet.